Summary ? The dysregulation of mitochondrial networks responsible for maintaining normal metabolism is an established hallmark of cancer and an early event in tumorigenesis. The disruption of cell metabolism leads to accumulation of reactive oxygen species (ROS) and triggers maladaptive signaling that disrupts metabolic balance, which can establish a tumorigenic and/or therapy resistant phenotype. In this regard, a subgroup of estrogen receptor-positive (ER+) breast malignancies, which exhibit increased ROS levels and a high risk of recurrence due to tamoxifen resistance (TamR), has been identified. We recently identified a novel mitochondrial signaling axis centered on manganese superoxide dismutase (MnSOD) which, when the acetylation (Ac) status of lysine 68 (K68-Ac) is altered, disrupts cell metabolism, leading to aberrant ROS levels (Zhu, Nature Commun., 2019). In addition, breast cancer cells expressing a MnSOD-K68-Ac mimic mutant (MnSODK68Q) exhibited increased HIF2? (known to promote stemness-like properties), increased SOX2 and Oct4 (two established stem cell biomarkers), and displayed increased oncogenicity and TamR - implying that disruption of cell metabolism reprograms tumors to exhibit a stemness-like phenotype. Based on our new data, our recent publication (Zhu et al, Nature Commun. 2019), and work by others, it is hypothesized that dysregulated MnSOD biology, due to aberrant/increased MnSOD-K68-Ac levels, disrupts normal cellular and mitochondrial metabolism. This initiates metabolic reprogramming, via increased levels of HIF2?, leading to a cell stemness-mediated tumor-permissive and/or TamR phenotype.Thus, we seek to further explore how MnSOD-K68-Ac disrupts cell metabolism and promotes a stemness-like phenotype, leading to oncogenicity and/or TamR. Finally, will GC4419 exposure, a chemical SOD detoxification mimic, reverse the oncogenic and/or TamR phenotypes?